1. Field of the Invention
The present invention relates to a novel compound having an excellent antimicrobial activity against various pathogenic bacteria including drug-resistant bacteria and phytopathogenic bacteria or having an enzyme inhibitory activity against enzymes of the above bacteria, a method for producing the novel compound, use of the novel compound, and a novel microorganism that produces the novel compound.
2. Description of the Related Art
Conventionally, numerous antimicrobial agents have been used as therapeutic drugs for bacterial infectious diseases. Many of the conventionally known antimicrobial agents act on bacteria by inhibiting, for example, their nucleic acid synthesis, protein synthesis and peptide glycan synthesis. Their targeting site is only one, and they mainly aim to inhibit metabolic synthesis pathway. Thus, bacteria that are resistant to these antimicrobial agents easily appear. Particularly in recent years, multidrug resistant bacteria appear that are resistant to a plurality of antibiotics, which is problematic.
For example, as one clinically important problem, Staphylococcus aureus, which is known as bacteria causing suppurative diseases, pneumonia and food poisoning, acquires multidrug resistances to methicilline or other antibiotics to be methicilline-resistant Staphylococcus aureus (MRSA). At present, vancomycin, teicoplanin, arbekacin, linezolid, etc. are used as typical therapeutic drugs against MRSA. However, it is generally difficult to completely eliminate MRSA. In particular, thorough care should be taken about the use of vancomycin, since appearance of vancomycin resistant Staphylococcus aureus (VRSA) has already been reported.
In order to overcome such problems relating to drug-resistant bacteria, demand has arisen for the development of a novel antimicrobial agent that acts on target microorganisms through a new mechanism different from those of the conventional antimicrobial agents (see, for example, Sievert D M, et al: Staphylococcus aureus Resistant to Vancomycin-United States, 2002. MMWR Jul. 5, 2002; 51: 565-567).
Meanwhile, bacteria have known to possess signal transduction mechanisms in which receptors respond to and receive changes of the environment and then the expressions of the corresponding genes are controlled. One typical example of the signal transduction mechanisms is two-component systems. The two-component systems are systems that control the expressions of genes responsive to the environment and that are composed of sensor proteins exhibiting histidine kinase activity and regulators which are DNA-binding proteins. Bacteria have various sensors and regulators for responding to various changes in the environment (see, for example, Bioscience and industry, Vol. 58, No. 4).
Such two-component systems of bacteria are, for example, signal transduction mechanisms of Gram-positive bacteria involving YycF and YycG. As has been known, bacteria are killed by inhibiting the actions of YycF and YycG (see, for example, Fablet, C. and Hoch, A. A., J. Bacteriol., 180, 6375-6383, 1998; Marti, P. K., Li, T., Sun, D., Biek, D. P. and Schmid, M. B., J. Bacteriol., 181, 3666-3673, 1999; Lange, R., Wagner, C., DeSaizieu, A., Flint, N., Monos, J., Stiger, M., Caspers, P., Kamber, M., Keck wolfgang, Amrein, K. E., Gene, 237, 223-234, 1999; and Beier, D. and Frank, R., J. Bacteriol., 182, 2068-2076, 2000). Thus, a promising antimicrobial agent is one having antimicrobial activity against Gram-positive bacteria by inhibiting the above signal transduction mechanism.
Also, the pathogenicity of soft-rot bacteria, which infect agricultural crops (e.g., Chinese cabbages and potatoes) to cause severe damage to agricultural production, is known to be controlled by three two-component systems: PehS/PehR (see, for example, Eriksson, A. R. B., Andersson, R. A., Pirhonen, M., and Palva, E. T., Mol. Plant-Microbe Interact., 11, 743-752, 1998), PmrB/PmrA (see, for example, Hyytiainen, H., Sjoblom, S., Palomaki, T., Tuikkala, A., and Palva, E. T., Mol. Microbiol., 50, 795-807, 2003) and ExpS/ExpA (see, for example, Flego, D., Marits, R., Eriksson, A. R. B., Koiv, V., Karlsson, M.-B., Heikinheimo, R., and Palva, E. T., Mol. Plant-Microbe Interact., 13, 447-455, 2000). Thus, prevention/removal of soft-rot bacteria could be satisfactorily achieved by suppressing the pathogenicity.
Although the above-described findings have been obtained, satisfactory antimicrobial agents and enzyme activity inhibitors have not yet been obtained. Demand has presently arisen for the development of excellent antimicrobial agents, etc.